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(CB2R) Agonists Modulate Neuropathic Pain and Cytokine Expression Jenny Wilkerson

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University of New Mexico UNM Digital Repository Biomedical Sciences ETDs Electronic Theses and Dissertations 12-1-2012 Cannabinoid 2 receptor (CB2R) agonists modulate neuropathic pain and cytokine expression Jenny Wilkerson Follow this and additional works at: https://digitalrepository.unm.edu/biom_etds Recommended Citation Wilkerson, Jenny. "Cannabinoid 2 receptor (CB2R) agonists modulate neuropathic pain and cytokine expression." (2012). https://digitalrepository.unm.edu/biom_etds/68 This Dissertation is brought to you for free and open access by the Electronic Theses and Dissertations at UNM Digital Repository. It has been accepted for inclusion in Biomedical Sciences ETDs by an authorized administrator of UNM Digital Repository. For more information, please contact [email protected]. Jenny L. Wilkerson Candidate Biomedical Sciences- Department of Neurosciences Department This dissertation is approved, and it is acceptable in quality and form for publication: Approved by the Dissertation Committee: Erin D. Milligan, PhD, Chairperson James Wallace, PhD Lee Anna Cunningham, PhD Oscar Bizzozero, PhD i CANNABINOID 2 RECEPTOR (CB2R) AGONISTS MODULATE NEUROPATHIC PAIN AND CYTOKINE EXPRESSION by JENNY L. WILKERSON B.S. Biology, Northwest Missouri State University, 2004 DISSERTATION Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Biomedical Sciences The University of New Mexico Albuquerque, New Mexico November, 2012 ii Acknowledgements There are so many people that have helped me throughout my life, making my journey towards obtaining my doctorate possible. First, I need to recognize all those teachers that inspired and encouraged me throughout my schooling. In particular, my first grade teacher, Mrs. Trutzel, stands out, as she spent countless hours privately tutoring me in lesson areas where I needed help. Her tireless dedication to her students is both commendable and honorable in so many ways, and her contribution in my life is truly immeasurable. Secondly, I must acknowledge the team of physicians that mended a physically broken newborn so many years ago, and allowed me the chance of a normal life. It is those physicians, and the medical researchers that developed the life-saving surgical and critical care skills that allowed me to live, that has inspired me to dedicate my professional career towards medical research. My family has been so supportive in me reaching for my dreams throughout the years, even though I know it was bittersweet for them to watch me fly away. Thank you so much for always believing in me, and encouraging me to follow my dreams. My mother is truly amazing, as she allowed me the freedom to become my own person, and to find my own passions in life. I also owe my love of reading and books to my mom, as she ritually took me to our local library to participate in their summer reading program. Both my parents sacrificed so much, so that I may have a good life, and of which, I will never forget. In this time of remembrance, I must honor my late grandmother, Myra Lynn. I was blessed to have her a part of the first 15 years of my life. She was truly an inspiring, iii remarkable, thoughtful and kind person with incredible inner strength, and she is my most important role model. I count myself as blessed to have such phenomenal experiences from being in Girl Scouts, and special thanks goes out to my extended Girl Scout family- you are all amazing women. I am so thankful to both my family and my friends for the love, support, well-wishes, shoulders that were leaned on, and ears that were talked nearly off, throughout this process. My wonderful husband, Jesse, has been my rock and source of strength. Through the years we have been together, he has stood by me, comforted me, and put me and my goals first. He has been willing to follow me wherever I go in life, and does so many little things to help, to make me laugh, and to show his undying love, devotion and support. I cannot express in words how thankful I am to him, and I am excited to see where life takes us from here. The mentoring that I have received at the University of New Mexico has been terrific. I cannot say thank you enough to Dr. Maggie Warner-Washburne, and the UNM Initiatives to Maximize Student Diversity (IMSD) program for the financial support of my first two years of graduate work, and for the mentoring that did not cease after the program. Dr. Linda Saland and Dr. Jim Wallace are both incredible scientists and amazing people in the department of Neuroscience at UNM. They have provided so much guidance in my development as a scientist, and their dedication to teaching the next generation of physicians and basic scientists is evident in the interactions that I have had with each of them. My committee on studies has provided both wonderful praises, as well as a critical eye in my progress, and I greatly thank the members of my committee for iv both. Above all, I owe my P.I. and primary mentor, Erin Milligan, for molding and making me into the scientist that I have become. She has been a wonderful role model through the years. She has believed in me, guided me, and both mentally and financially supported me throughout my years in her laboratory. She pushed me to perform beyond my own initial expectations of myself, towards my true potential. Also, she has taught me to personally accept only the highest standards of excellence in my professional development. I am so grateful to have had her has my mentor. I also am very much indebted to all the past and present laboratory personnel that I have had the pleasure to work with and come to know. Each one of you, in your own way, left an indelible mark on me, and I thank you for helping me grow as a person, as a scientist, and where appropriate, as a mentor. I must acknowledge the aid that I received from Dr. Clark Bird from UNM department of Neuroscience in his assistance in designing my CB1R primers. I also must thank the marvelous support staff at UNM for so many ‘behind the scenes’ contributions. Thank you to the BSGP staff and the Neurosciences department staff for the administrative support that you have shown me through the years. Thank you to Buz Tyler, who has provided so much invaluable I.T. support, and the Cancer Resource Facility microscopy suite personnel for their expertise on microscopy. Also, a big thank you goes out to the Animal Resource Facility and its staff in doing what you all do, because without it I would not have been able to complete my dissertation. v Table of Contents Dissertation Title Page ....................................................................................... ii Acknowledgements ........................................................................................... iii Abstract ............................................................................................................... x List of Figures .................................................................................................. xiii Abbreviations ...................................................................................................... 1 1. The central role of glia in pathological pain and the potential of targeting the cannabinoid 2 receptor for pain relief .................................................... 4 Abstract ............................................................................................................... 4 1.1 Normal vs. pathological pain ................................................................................................. 6 1.1.1 Acute Pain Signaling ...................................................................................................... 6 1.1.2 Central Sensitization ...................................................................................................... 7 1.1.3 Sensory Changes in Pathological Pain .......................................................................... 9 1.2 The role of glia in pathological pain ....................................................................................... 9 1.2.1 Glial activation ................................................................................................................ 9 1.2.2 Glial morphology and activation markers ..................................................................... 12 1.2.3 Downstream glial signaling of cytokines ...................................................................... 14 1.2.4 Glia in DRG .................................................................................................................. 17 1.2.5 Modulating glial activation for pain relief ...................................................................... 18 1.3 The endocannabinoid system .............................................................................................. 19 1.3.1 Components of the endocannabinoid system .............................................................. 19 1.3.2 Classical cannabinoid receptor signaling ..................................................................... 20 1.3.3 Cannabinoid 2 receptors .............................................................................................. 22 1.3.4 Bioavailability of endocannabinoids ............................................................................. 24 1.3.5 The implications of the endocannabinoid system in pain modulation .......................... 25 1.4 Well-characterized CB2R synthetic compounds .................................................................. 28 1.5 Newer CB2R
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